The present project will structurally and thermodynamically characterize many of the mutations in HIV- 1 protease that confer resistance to ritonavir. The nature of many of these mutations suggest the involvement of structural rearrangements, solvation effects, or entropic factors, requiring rigorous molecular simulation techniques to model. This project will entail advancing the ? about.-dynamics scheme to computationally explore mutations at multiple sites in a single mutation. As X-dynamics is a modified molecular dynamics algorithm, it contains the necessary elements to study these phenomena. Specifically, explicit solvent is used, bound and unbound simulations are considered, and full protein motion is simulated (allowing detection of changes in protein structure and dynamics). Furthermore, sampling is performed in a thermodynamically meaningful ensemble, such that relative free energies of binding can be obtained. In addition to providing insight into the mechanisms of resistance and potentially allowing for prediction of drug modifications that may improve protency, the methodologies used may prove useful in predicting the resistance profiles of lead compounds in future drug optimization scenarios.